AUTHOR=Mollo Nunzia , Nitti Maria , Zerillo Lucrezia , Faicchia Deriggio , Micillo Teresa , Accarino Rossella , Secondo Agnese , Petrozziello Tiziana , Calì Gaetano , Cicatiello Rita , Bonfiglio Ferdinando , Sarnataro Viviana , Genesio Rita , Izzo Antonella , Pinton Paolo , Matarese Giuseppe , Paladino Simona , Conti Anna , Nitsch Lucio TITLE=Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells JOURNAL=Frontiers in Genetics VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00606 DOI=10.3389/fgene.2019.00606 ISSN=1664-8021 ABSTRACT=

Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A, is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1) were upregulated while dynamin-related protein 1 (DRP1) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 μM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage.